The goals of this project are to elucidate the mechanisms of action of tumor viruses and to determine the cellular alterations responsible for naturally occurring malignancies. Topics of present interest include: (1) transforming genes of retroviruses and cancer cells; (2) the biology of endogenous retroviruses; (3) the molecular biology of retrovirus replication and transformation; and (4) the application of knowledge gained from these studies to the search for the causes and mechanisms involved in human neoplastic transformation. During the past year, we have isolated and partially characterized a number of new human oncogenes, and have gained important new insights regarding the structure and function of the sis and ras oncogenes. We have also made important progress in the exploitation of two animal lentiviruses as models for the human immunodeficiency viruses (HIV). Newly described oncogenes include the erbB-2 gene, isolated from a human breast carcinoma; dbl, isolated in a human diffuse B cell lymphoma; and arg, a member of the tryosine kinase family closely related to but distinct from c-abl. Another gene encoding transforming growth factor alpha (TGF alpha), a human growth factor, was characterized as having growth promoting potential but not to be a direct-acting oncogene. Lentivirus studies revealed their evolutionary relatedness to HIV and resulted in a collaborative drug therapy study which demonstrated the broad spectrum antiretroviral activity of the dideoxynucleosides. Protein kinase C was demonstrated to be activated by phorbol esters.